Neurotrophins are a unique family of poiypeptide growth factors that influence the proliferation, differentiation, survivaJ and death of neuronal and non-neuronal cells during vertebrate development. These proteins do not exist in Drosophila rnetanogaster or C elegans, even though other well known polypeptide growth factors, such as EGF, FGF and insulin, are conserved in these species and are required for many developmentaH events. The evolution of NGF, BDNF, NT-3 and NT-4 as a family implies these signaling molecules may act to mediate additional higher order activities, such as learning, memory and behavior, indeed, there is now abundant evidence that one of the neurotrophins, BDNF, is directly involved in synapse modification, neurotransrnitter release, Jong-term potentiation and mechanosensation. These new actions indicate that there must exist specialized receptor-mediated events to regulate these events. Neurotrophins reJy upon two types of receptors, Trk receptor tyrosine kinases and the p75 receptor. We have found a novel downstream substrate for the neurotrophin receptors that may account for the rapid and acute effects of neurotrophins. The substrate, called ARMS, is also modified by ephrins. It is likely that the information accumulated from receptor signaling from these factors witl lead to a greater understanding of presynaptic and postsynaptic actions of neurotrophins and ephrins. The research proposed in this subproject will be relevant to the understanding and treatment of neurodegenerative diseases, such as Parkinson's and AIzheirner's diseases and amyotrophic iateral sclerosis.